Despite aggressive multimodality therapy regimen, most pediatric patients with relapsed or primary metastatic solid tumors have a very poor prognosis which has not significantly changed in the past three decades. External beam radiation therapy is an instrumental part of treatment of most solid tumors, but has a limited applicability in the setting of disseminated disease. Injectable compounds that specifically deliver ionizing radiation to tumor cells have the potential to effectively treat metastatic diseas, but for most pediatric tumors those drugs do not exist. CLR1404 is a novel, broadly tumor-targeting phospholipid ether analog which enters cancer cells via specialized plasma membrane micro-domains called lipid rafts. Malignant cells contain much higher amounts of lipid rafts than do normal cells, resulting in the preferential accumulation of the drug in extra- and intracellular cell membranes. Pre-clinical toxicology studies in rodents and non-human primates have demonstrated a very favorable toxicity profile. Our preliminary data demonstrate significant uptake of CLR1404 in various pediatric tumor lines in vitro and in vivo while the drug is sparing healthy tissue. CLR1404 has been radio-iodinated for tumor-selective PET/CT imaging (124I-CLR1404) and tumor-specific radiotherapy (131I-CLR1404) and has entered clinical trials in adult cancers at our institution. We hypothesize that the radio-iodinated derivative, 131I-CLR1404, is a suitable drug for molecular radiotherapy of pediatric solid cancers. Our application aims at providing the necessary pre-clinical data to initiate a pediatric trial. Therefore, we will investigate this drug in mouse xenograft models of four pediatric tumors with particularly poor survival in disseminated disease or relapse (neuroblastoma, rhabdomyosarcoma, osteo-sarcoma and Ewing sarcoma). In neuroblastoma, we will compare 131I-CLR1404 to an established radioactive drug for imaging and treatment, 131I-MIBG (m-iodo-benzyl-guanidine). We will perform uptake and dosimetry studies using sophisticated Monte-Carlo-Simulation as a useful tool for pediatric clinical studies. We will evaluate tumor response to treatment with 131I-CLR1404 in mouse xenograft models to establish proof-of- principle for the in vivo activity of this novel molecular radio-therapeutic compound and provide the rationale for clinical protocol development. The non-radioactive compound 127I-CLR1404 interferes with pathways crucial in repair mechanisms after radiation injury in mass doses higher than used for radiotherapy and may act as a radio-sensitizer. Therefore, we will investigate whether combination therapy of 127I-CLR1404 with 131I-CLR1404 or 131I-MIBG leads to improved anti-cancer effects in vivo. Extensive pre- clinical data exist with CLR1404 for adult cancers and adult clinical trials have begun at our institution. We are confident that results obtained with our application that would support evaluation of 131I-CLR1404 in pediatric solid tumors can be translated into a clinical trial within 2-3 years.